The public health burden of diabetes mellitus and thyroid disease: twin epidemics.

INTRODUCTION Nonalcohol-associated hepatic steatosis, commonly termed NAFLD has emerged as an epidemic in the 21st century and has been proven to be associated with notable extrahepatic manifestations including cardiovascular disease (CVD), chronic kidney disease, hypothyroidism, and psoriasis.1 It is well understood that type II diabetes mellitus (DM) plays a critical role in the development and progression of NAFLD, but only recently has NAFLD been recognized as a risk factor for DM itself. Higher intrahepatic triglyceride content has been shown to be associated with an increased risk of DM, suggesting a pathogenic role of hepatic steatosis in DM evolution.2 This review aims to summarize the emerging evidence on the role of NAFLD in subsequent DM development and progression and to review the current diabetic therapies under investigation for treatment of NAFLD. EPIDEMIOLOGICAL EVIDENCE LINKING DM AND NAFLD NAFLD as an independent risk factor for DM was first reported in 2008, in a study that followed >5000 Korean adults for a period of 5 years.3 Over the last decade, several studies have confirmed this association. These analyses have been subsequently pooled in a meta-analysis of >500,000 individuals in 33 prospective cohorts over a median follow up of 5 years, a study which found that NAFLD confers a 2-fold higher risk for DM after adjustment for demographic factors, medical history, and behavioral risk factors known to be associated with DM.4 Data suggest the risk parallels the severity of NAFLD (in terms of both steatosis and fibrosis) with the highest risk seen amongst those with advanced liver fibrosis (HR=3.42 across 5 studies). A bias analysis to quantify unmeasured confounding was strongly suggestive of a causal link between NAFLD and DM.5 Furthermore, amongst >10,000 subjects, resolution of NAFLD presented a similar risk for DM as no NAFLD, whereas incident and persistent NAFLD were associated with a higher risk for DM, thereby suggesting a potential causal relationship.6 Notably, NAFLD was associated with an 80% higher risk of progression to overt DM in >6000 subjects with prediabetes as compared to those without NAFLD after adjusting for several metabolic risk factors.7 Although data suggest NAFLD as a risk factor for incident DM, it is important to note the limitations of observational studies proposing this relationship and to emphasize the need for further investigation to establish causality. Inversely, DM is a well-established risk factor for NAFLD development and progression. Prevalence of NAFLD in DM diagnosed by liver biopsy and ultrasonography was reported to be 91.6% and 59.2%, respectively.8 PATHOPHYSIOLOGICAL MECHANISM FOR DM DEVELOPMENT IN NAFLD The exact pathogenesis for the increased risk of DM in NAFLD is unknown. The liver proactively mediates glucose metabolism by an insulin-dependent process and is intricately involved in glucose homeostasis via gluconeogenesis, glycogenolysis, and glycogen synthesis. Distinct mechanisms, including an adipocyte-liver axis [excess delivery of free fatty acids, de novo lipogenesis (DNL)] and an altered gut-liver axis (altered bile acid and microbial profiles) are postulated to drive the relationship (Figure 1).9FIGURE 1: Proposed pathogenesis of diabetes mellitus in NAFLD. Free fatty acids (FFA) from adipose tissue and/or dietary sources are converted to ceramides and diacylglycerols (DAG). Ceramides and DAG impair hepatic insulin signaling, activate protein kinase C (PKC) and increase oxidative stress. This results in hepatic insulin resistance (IR) and a systemic inflammatory state eventually leading to hyperglycemia. Further coupled with intestinal dysbiosis, altered bile acid profile and decreased insulin clearance from hepatic fat deposition eventually lead to beta-cell dysfunction and incident diabetes mellitus.TG, triglyceride.Insulin resistance (IR) is a clear predisposing factor for DM and has been shown to manifest a cause-effect relationship with NAFLD. In fact, IR is observed almost universally in NAFLD patients, including those with lean NAFLD.10 Early in the pathogenesis, excessive hepatic fat deposition impairs hepatic insulin signaling, resulting in hepatic IR and excessive gluconeogenesis, both characteristic features of DM.9 Lipid deposition, especially diacylglycerol and ceramide, exacerbates hepatic IR via activation of hepatic protein kinase C, leading to a proinflammatory state termed lipotoxicity.11 Lipotoxicity results in endoplasmic reticulum stress, mitochondrial dysfunction, impaired autophagy, and release of extracellular vesicles ultimately leading to cell death.12 Proinflammatory cytokines (TNFα, IL-6, monocyte chemoattractant protein-1, resistin and plasminogen activator inhibitor-1) are also elevated in NAFLD and have been shown to exacerbate both hepatic and systemic IR.13 In addition, hepatic insulin clearance (which accounts for 50%–80% of total insulin clearance) has been reported to be decreased in NAFLD, and is directly related to systemic IR.14 Moreover, IR promotes excessive DNL from dietary and peripherally derived substrates in NAFLD, which further provokes hepatic IR, thereby perpetuating a vicious cycle (Figure 1). Gut dysbiosis via bile acid profile alteration and induction of inflammation also plays a role in the development of hepatic IR. After intestinal conjugation, bile acids modulate insulin secretion (via the TGR5 receptor), decrease hepatic lipid accumulation, and suppress hepatic gluconeogenesis (via the FXR receptor).13 This pathway is reported to be altered in NAFLD. Systemic and hepatic IR, hyperinsulinemia and resultant glucotoxicity and lipotoxicity also lead to pancreatic beta-cell dysfunction, reduced beta-cell mass, and eventually overt DM (Figure 1). IMPACT ON DISEASE PROGRESSION With a shared pathophysiology, it is not surprising that the presence of either of 2 conditions, NAFLD or DM, is associated with progression of the other (Figure 2). On one hand, DM is a well-established risk factor for NASH, advanced fibrosis, hepatocellular carcinoma and all-cause mortality in NAFLD.12 On the other, recent data suggest NAFLD as an emerging risk factor for development of both macrovascular and microvascular complications as well as mortality in DM. In a prospective study, NAFLD doubled the mortality risk in 337 patients with DM after adjustment for known DM-related, cardiometabolic, and demographic risk factors.15FIGURE 2: Bidirectional relationship between NAFLD and type II diabetes mellitus (DM). DM drives NAFLD progression whereas NAFLD exacerbates microvascular and macrovascular DM complications.Both clinical and subclinical CVD is reported to be higher in patients with DM and NAFLD compared to DM patients without NAFLD.5 In >2000 outpatients with DM in the Valpolicella Heart Diabetes Study, NAFLD was associated with a 2 times higher incidence of fatal and nonfatal CVD.16 Rates and severity of coronary artery disease, arrhythmias and valvular heart disease have also been reported to be higher in DM patients with NAFLD.17 Similarly, prevalent and incident rates of chronic kidney disease in DM have been demonstrated to be higher in NAFLD patients, with rates observed to increase associative with the severity of NAFLD.17 In a longitudinal study of 1760 patients with DM, NAFLD conferred a 69% higher risk of developing chronic kidney disease independent of severity or duration of DM.18 Data regarding other microvascular complications including retinopathy and neuropathy is mixed. It is critical to emphasize that most studies are cross-sectional and cannot establish causality, which requires further investigation. IR and the associated hepatic and systemic inflammatory state seen in NAFLD are hypothesized to raise the risk of aforementioned DM-related complications. Hepatic IR-driven DNL increases the synthesis of diacylglycerol and ceramides. These molecules effect the release of proinflammatory cytokines and procoagulant factors, known to be associated with atherogenic dyslipidemia and myocardial remodeling.17 These in turn have been postulated to promote cardiovascular complications in DM. On the other hand, glucotoxicity augments DNL, exacerbates lipotoxity and promotes hepatic inflammation and progression of NAFLD to NASH.9 Early diagnosis and intervention for NAFLD in DM can potentially lower the risk of DM-associated complications. In sum, NAFLD can theoretically serve as a prognostic marker and therapeutic target in DM and prediabetes. ANTIDIABETIC DRUGS AS AVENUES FOR NAFLD TREATMENT In addition to physical activity and dietary measures that are integral to the management of both NAFLD and DM, antidiabetic agents hold potential as therapeutic agents in NAFLD. Glucagon-like peptide 1 agonists and sodium glucose cotransporter 2 inhibitors, which have become front line therapy for DM, have shown benefit in NASH resolution, hepatocellular lipid content and liver biochemical test improvement.19,20 Peroxisome proliferator-activated receptor agonist, another class of DM agents, have resurfaced as potential therapeutic options, with studies showing improvement in liver histology and reduction in NASH.21Table 1 summarizes clinical trials, either underway or completed, in the last 5 years, which have evaluated the effect of antidiabetic agents on either histological or MRI-defined NAFLD outcomes. TABLE 1 - Clinical trials, either underway or completed, in the last 5 years, which have evaluated the effect of antidiabetic agents (ADAs) on either histological or MRI-defined NAFLD outcomes Drug CT identifier Acronym Year Participants (n) Sites (n) Duration (wk) Primary outcomes GLP agonist Semaglutide NCT05067621 2022 60 1 24 Percent change in hepatic fat fraction by MRI-PDFF Semaglutide+FGF21 analog NCT05016882 2021 672 136 52 Improvement in fibrosis defined as ≥1-grade improvement on the NASH CRN fibrosis scale Semaglutide NCT04822181 ESSENCE 2021 1200 370 72 1. One stage of improvement in fibrosis without worsening NASH 2. Resolution of NASH without worsening of fibrosis 3. Time to first liver-related clinical event (till week 240) Semaglutide±cilofexor/fircostat NCT04971785 2021 440 100 72 1. One stage of improvement in fibrosis without worsening of NASH 2. Resolution of NASH without worsening of fibrosis Efinopegdutide (GLP-1/glucagon receptor dual agonist) vs. Semaglutide NCT04944992 2021 130 69 24 Percent change in hepatic fat fraction by MRI-PDFF GLP-1 analog (BI456906) NCT04771273 2021 240 157 48 Percentage of patients with NAS reduction of 2 or more points with histological improvement of NASH Glucagon/GIP/GLP-1 analog (HM15211), triple acting agent NCT04505436 2020 217 46 52 30% reduction in liver fat from baseline by MRI-PDFF Semaglutide NCT03919929 2019 50 1 12 Percent change in hepatic fat fraction by MRI-PDFF Tirzepatide (dual glucose-dependent insulinotropic polypeptide and GLP-1 agonist NCT04166773 2019 196 119 52 Percentage of participants with absence of NASH with no worsening of fibrosis on liver histology Semaglutide NCT03987451 2019 71 38 48 At least 1 stage of liver fibrosis improvement with no worsening of NASH Semaglutide NCT03884075 2019 84 1 30 1. Histological improvement ≥2 point decrease in NAS 2. Clinical improvement (time frame: 30 wk) 3. Reduction of liver fat content (measure with 1H-magnetic resonance spectroscopy) by ≥25% and 4. Reduction of ALT by ≥25% or normalization of ALT SGLT inhibitor Dapagliflozin NCT05254626 2022 160 1 24 Reduction of at least 2 points in NAS in 2 histological categories without worsening of fibrosis on liver biopsy Empagliflozin NCT04642261 2021 98 1 52 Percent change in hepatic fat fraction by MRI-PDFF Empagliflozin NCT04910178 2021 80 1 NR Percent change in hepatic fat fraction by MRI-PDFF Empagligflozin±semaglutide vs. placebo NCT04639414 COMBATT2NASH 2021 192 30 48 Histological resolution of NASH without worsening of fibrosis Licogliflozin±tropifexor vs. placebo NCT04065841 ELIVATE 2019 380 130 48 1. One stage of improvement in fibrosis without worsening of NASH 2. Resolution of NASH without worsening of fibrosis Dapagliflozin NCT03723252 DEAN 2019 100 1 52 Improvement in scored liver histological improvement Empagliflozin±pioglitazone NCT03646292 2018 60 1 24 Percent change in hepatic fat fraction by MRI-PDFF Thiazolidinedione/PPAR agonist Saroglitazar NCT05011305 2021 240 5 76 Resolution of steatohepatitis defined as absent fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS of 0–1 for inflammation, 0 for ballooning, and any value for steatosis Pioglitazone (lower dose of 15 mg day) NCT04501406 AIM 2 2020 138 1 72 Improvement of ≥2 points NAS without an increase in fibrosis stage Saroglitazar NCT03863574 EVIDENCES VI 2019 16 1 24 Assess the changes in NAS at week 24 from baseline and with no worsening of fibrosis Lanafibrinor NCT03459079 2018 44 1 24 Change in intrahepatic triglycerides quantified by proton magnetic resonance and spectroscopy (¹H-MRS) Saroglitazar NCT03617263 EVIDENCES VII 2018 90 15 24 Percent change in hepatic fat fraction by MRI-PDFF Pemafibrate (0.2 mg BID) NCT03350165 2017 118 16 24 Percent change in hepatic fat fraction by MRI-PDFF Oral insulin Oral insulin NCT02653300 2018 10 1 12 Percent change in hepatic fat fraction by MRI-PDFF DPP-IV inhibitor Nesinaact (Alogliptin benzoate 25 mg, pioglitazone hydrochloride 15 mg) NCT03950505 2019 60 1 24 Percent change in hepatic fat fraction by MRI-PDFF Abbreviations: DPP-IV, dipeptidyl peptidase-IV; GLP, glucagon-like peptide; MRI-PDFF; magnetic resonance imaging-proton density fat fraction; NAS, NAFLD activity score; PPAR, peroxisome proliferator-activated receptor; SGLT, sodium glucose cotransporter. CONCLUSION The bi-directional relationship of the development and progression of NAFLD and DM is clinically relevant to hepatologists, endocrinologists, and primary care physicians. The presence of NAFLD can serve as a marker to identify patients at high risk of developing DM and of subsequent diabetic complications. Modulation of IR early in NAFLD has the potential to serve as a therapeutic strategy to prevent disease progression in these 2 highly prevalent conditions. Future studies to identify the subgroups of NAFLD patients at higher risk of DM may facilitate early prediction and subsequent intervention to reduce the risk of DM and progression.

The two most prevalent endocrine-related conditions seen in clinical practice are thyroid diseases (TD) and diabetes mellitus (DM). Diabetes mellitus and thyroid dysfunction are strongly related conditions. Numerous research investigations have reported that individuals with diabetes mellitus are more likely to have thyroid issues, and vice versa. Compared to individuals without diabetes, Type 2 Diabetes Mellitus (T2DM) patients have higher rates of both hypothyroidism and hyperthyroidism. Thyroid hormones are circulating hormones that impact various organs and tissues, have a vital role in the metabolism of proteins, fats, and carbohydrates, and can exacerbate glycemic control in individuals with Type II Diabetes Mellitus (T2DM). At the Specialized Center for Endocrinology and Diabetes – Al-Kindi Teaching Hospital in Baghdad, a case-control research was carried out. The samples were gathered between January 1, 2021, and April 1, 2021. The current study had one hundred twenty (120) volunteers, all of whom fasted for eight to twelve hours before to the test: · Thirty (30) patients suffered from diabetic mellitus type II seventeen (17) females and thirteen (13) males. · Thirty (30) were control with, sixteen (16) females and fourteen (14) males. · Thirty (30) patients had thyroid dysfunction eighteen (18) females and twelve (12) males. · Thirty (30) patients had thyroid dysfunction and diabetes mellitus type II, sixteen (16) females and fourteen (14) males. Variables such as gender, age, Body Mass Index (BMI), thyroid hormones ,Fasting Blood Sugar (FBS), Glycated Hemoglobin (HbA1c), lipid profile (TG, CHOL, LDL-C, HDL-C, VLDL-C), Adiponectin (ADP)were measured and documented from participants included in this study. According to the results of hormones, there were substantial variations in all of the hormone levels. Thyroid Stimulating Hermon (TSH) was the highest level in Thyroid Dysfunction with Diabetes Mellitus type II: Hypothyroidism patients(0.46 ± 6.26) µIU/mL. T3 hormone was (187.84 ± 6.12) ng/dL, the highest resultin Thyroid Dysfunction with Diabetes Mellitus type Ⅱ: Hyperthyroidism patients. T4 was highest hormonal level in Thyroid Dysfunction with Diabetes Mellitus type II: Hyperthyroidism patients which was (14.02 ± 0.56) ng/dL. Fasting blood sugar (serum) measured a highly significant differences and highest level in patients who suffered from thyroid Dysfunction with Diabetes Mellitus type II: Hypothyroidism with (190.50 ± 12.72) mg/dL. Glycated hemoglobin (HbA1c) measured high significant differences with (11.13 ± 0.55) mmoL/L in patients of diabetes type II. Cholesterol, Triglyceride, LDL-C and VLDL-C high significant differences and highest levels were among patients with Thyroid Dysfunction with Diabetes Mellitus type II: Hypothyroidism with (209.45 ±12.29, 268.18 ±31.57, 114.24 ±13.74 and 55.98 ±5.63) mg/dL respectively, while HDL-C was significantly higher in control group. The Adiponectin had high significant differences among Thyroid Dysfunction: Hyperthyroidism patients with (17.98 ±1.43) ng/mL. In conclusion this data backs up the theory that inducing or suppressing adiponectin in individuals with thyroid dysfunction can help them in losing weight. Hypothyroid individuals with DM Type II and lipid abnormalities in their blood. This data is attributed to the idea that inducing or suppressing adiponectin in individuals with thyroid dysfunction might be a promising new treatment strategy. Adiponectin has been shown that’s involved in numerous physiological and pathological processes, including as inflammation and tissue remodeling. They may be crucial in the formation of adipose tissue and insulin resistance, and they have been linked to a number of inflammatory illnesses.

The effect of cinnamon extract on insulin resistance parameters in polycystic ovary syndrome: a pilot study

Selective Insulin and Leptin Resistance in Metabolic Disorders

Background: Type 2 Diabetes Mellitus (T2DM), a prevalent metabolic disease, is characterized by chronic hyperglycemia and insulin resistance. Diabetic patients frequently experience thyroid dysfunction, which has an impact on their metabolic condition. The goal of this study is to evaluate the thyroid state of T2DM patients and look into the link between insulin resistance and thyroid hormone levels. Methods:The study included 30 male participants aged 30 to 60 years who were diagnosed with T2DM using the American Diabetes Association's (ADA) criteria. Insulin resistance was determined using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Thyroid function tests, including serum Thyroid Stimulating Hormone (TSH), Triiodothyronine (T3), and Thyroxine (T4) levels, were performed. Patients were divided into three groups based on their HOMA-IR values: low (≤2.5), moderate (2.5-4.0), and high (>4.0). Statistical analysis was used to determine the relationship between insulin resistance and thyroid hormone levels. Results: The study population's mean age was 51.9 ± 5.94 years. Our study denotes that Insulin resistance, as depicted by HOMA-IR correlates positively with TSH levels (r = 0.50). T4 correlates positively with TSH (r = 0.545) and T3 correlates well with T4 (0.598). Insulin resistance correlates positively with TSH levels (r = 0.50) Conclusion: This study confirms that insulin resistance in T2DM is associated with moderately enhanced levels of TSH, T3, and T4. The positive correlation between HOMA-IR and thyroid hormone levels suggests that insulin resistance may influence thyroid function. Regular thyroid status monitoring in T2DM patients is critical for early detection and management of thyroid dysfunction, which could improve overall metabolic control and quality of life. Further research is needed to determine the underlying mechanisms that link insulin resistance and thyroid dysfunction in T2DM.

Background: Thyroid dysfunction is an endocrine disorder with a recognized association with type 2 diabetes mellitus. Thyroid hormones have a remarkable effect on glucose metabolism and can cause insulin resistance (IR). This study was aimed at assessing the relationship between IR and thyroid dysfunction. Methods: This case–control study was conducted at the endocrinology outpatient clinics of Ibrahim Malik Hospital and Omdurman Military Hospital in Khartoum State, Sudan between May 2018 and January 2019. Fasting blood glucose (FBG), fasting insulin level, and thyroid function test (TFT) were measured for each candidate and IR was estimated using the HOMA-IR equation. Results: Thirty-one patients with thyroid dysfunction and fifty-seven control participants were enrolled. The highest mean FBG was found among cases (105.3 ± 15.7 mg/dl) compared to the controls (97 ± 12.1 mg/dl), but the difference was not statistically significant (P-value = 0.598). The mean fasting insulin level was 9.22 ± 4 IU/ml in the cases and 9.4 ± 4.2 IU/ml in controls, without a significant difference (P-value = 0.681). The highest HOMA-IR score was found among cases (2.4 ± 1.2). It was 2.4 ± 1.3 in hyperthyroidism, 2.3 ± 1.1 in hypothyroidism, and 2.4 ± 1.2 in controls, and the difference was insignificant (P-value = 0.859). IR was higher in the cases (58.1%) compared to the controls (52.6%) but again not statistically significant (P-value = 0.396). Among cases, IR was encountered in 61.9% and 50% of hyperthyroid and hypothyroid patients, respectively. Conclusion: Patients with thyroid dysfunction have some level of IR that was not statistically significant when compared with controls.

Вступ. Останні десятиліття характеризуються значним збільшенням частоти захворювань органів ендокринної системи зі зміною структури, насамперед випадків поліендокринопатій, особливе місце серед яких займають поєднання цукрового діабету (ЦД) і тиреопатій. Збільшення частоти поєднання ЦД 2-го типу з гіпотиреозом впливає на особливості клінічного перебігу такої патології, залишається актуальною проблемою сучасної медичної науки. Мета дослідження: вивчення частоти гіпотиреозу у хворих на ЦД 2-го типу та встановлення клінічних особливостей перебігу ЦД 2-го типу у поєднанні з гіпотиреозом. Матеріали і методи. Проведено обстеження 179 хворих на ЦД у поєднанні з первинним гіпотиреозом, у тому числі 64 хворих на ЦД 1-го типу і 115 хворих на ЦД 2-го типу. Групу порівняння становили 62 хворі на ЦД без гіпотиреозу (з них 27 — із ЦД 1-го типу, 35 — із ЦД 2-го типу). Функціональний стан щитоподібної залози (ЩЗ) оцінювали за допомогою визначення базальних концентрацій тиреотропного гормона і вільної фракції тироксину. Результати. Встановлено, що пацієнти із ЦД 2-го типу та гіпотиреозом належали до більш старшої вікової категорії, ніж пацієнти з ЦД 1-го типу та гіпотиреозом. Так, вік пацієнтів у групі хворих на ЦД 1-го типу з гіпотиреозом становив 35,3 ± 9,5 року та у групі хворих на ЦД 2-го типу з гіпотиреозом — 47,6 ± 11,0 року. В усіх групах хворих відсоток жінок був значно вищим за чоловіків. Виявлено вірогідні відмінності щодо показника амплітуди глікемії — його збільшення у хворих на ЦД 1-го типу з гіпотиреозом. При поєднанні ЦД 2-го типу з гіпотиреозом показники ліпідного обміну були вищими, ніж при ЦД 2-го типу без тиреоїдної патології. Це підтверджує вплив гіпотиреозу на ліпідний обмін та обумовлює підвищення ризику прогресування серцево-судинних ускладнень за наявності двох захворювань. Висновки. Серед обстежених хворих гіпотиреоз траплявся у 2,4 раза частіше при ЦД 2-го типу, ніж при ЦД 1-го типу, що свідчить про більше число чинників ризику розвитку супутньої автоімунної патології за умов метаболічних порушень при ЦД 2-го типу. Інсулінорезистентність та гіперінсулінемія, що відзначаються при ЦД 2-го типу, сприяють проліферативним процесам, у тому числі й у тканині ЩЗ, а більш старший вік хворих на ЦД 2-го типу сприяє прогресуванню інволютивних змін і подальшому розвитку гіпофункції ЩЗ. Рекомендується обов’язкове комплексне обстеження хворих на ЦД 2-го типу щодо наявності супутньої тиреоїдної патології.

The aim: The study aimed to determine the prevalence of several non-communicable diseases (NCD) and analyze risk factors among adult patients seeking nutritional guidance in Dhaka, Bangladesh. Participants: 146 hospitalized adults of both genders aged 18-93 participated in this cross-sectional research. Methods: We collected the demographic and vital information from 146 hospitalized patients in Dhaka, Bangladesh. We checked the physical and vital parameters, including blood sugar, serum creatinine, blood pressure, and the presence or absence of major non-communicable diseases. Then we used descriptive statistical approaches to explore the NCDs prevalence based on gender and age group. Afterwards, the relationship between different NCD pairs with their combined effects was analyzed using different hypothesis testing at a 95 % confidence level. Finally, the random forest and XGBoost machine learning algorithms are used to predict the comorbidity among the patients with the underlying responsible factors. Result: Our study observed the relationships between gender, age groups, obesity, and NCDs (DM, CKD, IBS, CVD, CRD, thyroid). The most frequently reported NCD was cardiovascular issues (CVD), which was present in 83.56 % of all participants. CVD was more common in male participants. Consequently, male participants had a higher blood pressure distribution than females. Diabetes mellitus (DM), on the other hand, did not have a gender-based inclination. Both CVD and DM had an age-based progression. Our study showed that chronic respiratory illness was more frequent in middle-aged participants than in younger or elderly individuals. Based on the data, every one in five hospitalized patients was obese. We analyzed the comorbidities and found that 31.5 % of the population has only one NCD, 30.1 % has two NCDs, and 38.3 % has more than two NCDs. Besides, 86.25 % of all diabetic patients had cardiovascular issues. All thyroid patients in our study had CVD. Using a t-test, we found a relationship between CKD and thyroid (p-value 0.061). Males under 35 years have a statistically significant relationship between thyroid and chronic respiratory diseases (p-value 0.018). We also found an association between DM and CKD among patients over 65 (p-value 0.038). Moreover, there has been a statistically significant relationship between CKD and Thyroid (P<0.05) for those below 35 and 35-65. We used a two-way ANOVA test to find the statistically significant interaction of heart issues and chronic respiratory illness in combination with diabetes. The combination of DM and RTI also affected CKD in male patients over 65 years old. Among machine learning algorithms, XGBoost produced the highest accuracy, 69.7 %, in comorbidity detection. Random forest feature importance detected age, weight and waist-hip ratio as the major risk factors behind the comorbidity. Conclusion: The prevalence study helps to identify the future risks and most vulnerable groups. By initiating and implementing control plans based on the prevalence study, it is possible to reduce the burden of NCDs on the elderly and middle-aged population of Bangladesh.

BackgroundThe choices that policymakers make are shaped by how their problems are framed. At last, non-communicable diseases (NCDs) have risen high on the global policy agenda, but there are many disputed issues. First, what are they? Their name refers not to what they are but what they are not. Second, where do their boundaries lie? What diseases are included? Third, should we view their causes as mainly biomedical, behavioural, or social, or a combination? Our failure to resolve these issues has been invoked as a reason for our limited progress in developing and implementing effective remedies. In this scoping review, we ask “What is known from the existing literature about how NCDs are framed in the global policy discourses?” We answer it by reviewing the frames employed in policy and academic discourses.MethodsWe searched nine electronic databases for articles published since inception to 31 May 2019. We also reviewed websites of eight international organisations to identify global NCDs policies. We extracted data and synthesised findings to identify key thematic frames.ResultsWe included 36 articles and nine policy documents on global NCDs policies. We identified five discursive domains that have been used and where there are differing perspectives. These are: “Expanding the NCDs frame to include mental health and air pollution”; “NCDs and their determinants”; “A rights-based approach to NCDs”; “Approaches to achieving policy coherence in NCDs globally”; and “NCDs as part of Sustainable Socio-economic Development”. We further identified 12 frames within the five discursive domains.ConclusionsThis scoping review identifies issues that remain unresolved and points to a need for alignment of perspectives among global health policy actors, as well as synergies with those working on mental health, maternal health, and child health. The current COVID-19 pandemic warrants greater consideration of its impact on global NCDs policies. Future global strategies for NCDs need to consider explicitly how NCDs are framed in a changing global health discourse and ensure adequate alignment with implementation and global health issues. There is a need for global strategies to recognise the pertinent role of actors in shaping policy discourses.

Overweight and obesity rates are consistently increasing worldwide. Many countries, including Australia report higher increases in obesity rates in women compared to men. In particular, weight gain in younger, reproductive aged women is escalating. Obesity, being an insulin resistant state, has serious health consequences. Traditionally, the focus has been on type II diabetes and cardiovascular disease in older individuals. However, in women of reproductive age, adverse lifestyle, obesity and insulin resistance has significant reproductive health implications that often occur well before type II diabetes. These include polycystic ovary syndrome and gestational diabetes mellitus in pregnancy. With high rates of weight gain and clear complications, young women present an important target group for intervention strategies. Insulin resistance is challenging to assess and relevant literature and novel new methods are explored early in the thesis. I then aimed to explore the role of lifestyle change and increased physical activity in two groups of overweight reproductive aged women with insulin resistance; women with polycystic ovary syndrome (PCOS) and pregnant women at high risk for developing gestational diabetes mellitus (GDM). As lifestyle improvement including exercise is highly effective in alleviating insulin resistance in other high risk groups, the studies presented in this thesis have a focus on promoting and evaluating healthy lifestyle and physical activity as a primary theme. I performed an extensive systematic literature review which highlighted research gaps and set the context for our intervention study in PCOS. In a comprehensive mechanistic study in overweight women with and without PCOS, intensified exercise training was evaluated without specified dietary prescription over 12 weeks. I assessed the effects on the key outcome measures; insulin resistance and body composition. This comprehensive study demonstrated worsened insulin resistance in PCOS women compared to non-PCOS control women. Following exercise, insulin resistance improved in both groups without change in weight suggesting the value of exercise in PCOS exceeds its impact on weight alone. Reproductive function also improved with exercise in PCOS women. Women with PCOS showed reduced visceral fat following exercise which is linked to insulin resistance; with no change in the control group. Despite reduced levels of visceral fat and improved insulin resistance, women with PCOS still had greater insulin resistance following exercise in comparison to controls. This study advanced the understanding of insulin resistance in PCOS but also highlighted the need to further mechanistically explore intrinsic insulin signalling defects in PCOS and evaluate the role of exercise in PCOS. In a large randomised controlled public health trial with overweight and obese pregnant women at risk for GDM, a healthy lifestyle program promoting increased physical activity, behaviour change and simple key messages related to improving diet was applied from early pregnancy to six weeks postpartum to assess key outcome measures including gestational weight gain, GDM incidence and physical activity levels. Pregnant women at increased risk for GDM were identified by the development and implementation of a risk screening tool. This Healthy Lifestyle Program (HeLP-her) in pregnancy study is modified from a previously successful intervention in mothers of school children developed by my supervisors and is set in a hospital setting. We have successfully recruited over 200 women (May 2008 – Oct 2010), with 166 of these having completed final data collection. The study is currently ongoing however interim results are presented in this thesis. I have investigated optimal measurement of physical activity in pregnancy, confirming the accuracy of pedometers in this setting. In the setting of a randomised controlled trial with the results of intervention still to be revealed, I have evaluated key lifestyle behaviours in women during pregnancy in the control group not receiving the intervention; drawing on key characteristics of women recruited for this study, describing early pregnancy weight gain, early pregnancy health behaviours and GDM incidence. Results to date demonstrate excess weight gain, a high GDM prevalence and sedentarism in early- to mid- pregnancy, highlighting the urgent need for lifestyle intervention in this high-risk group. The studies presented in this thesis add significantly to the literature, in young, insulin resistant women. The findings provide further evidence that lifestyle change incorporating increased physical activity is important for targeting insulin resistance, particularly in overweight women with PCOS. Final results are pending for lifestyle intervention in women at risk for GDM; however results to date demonstrate increased weight gain in early pregnancy and development of adverse health as evident by a high GDM incidence, mandating increased public health action towards improving lifestyle in this high-risk group. I have successfully finalised recruitment and await the results from the GDM intervention trial which will allow future clarification of the role of lifestyle change in overweight and obese insulin resistant pregnancies. Our group is building on the work presented in this thesis and has successfully obtained NHMRC funding to extend the intensified exercise training program in PCOS women to explore the effects in lean PCOS women. Additionally, we have also adapted the healthy lifestyles program to other populations at-risk, including women with PCOS, those with diabetes and high-risk ethnic subgroups. The findings presented in this thesis have made a significant contribution to women’s health, in settings where insulin resistance is present, creating an evidence base for the importance of lifestyle change in insulin resistant, reproductive aged women.

One of the most important characteristics of type 2 diabetes is insulin resistance, during which the patients normally experienced hyperinsulinism stress that would alter insulin signal transduction in insulin target tissues. We have previously found that early growth responsive gene-1 (Egr-1), a zinc finger transcription factor, is highly expressed in db/db mice and in the fat tissue of individuals with type 2 diabetes. In this report, we found that chronic exposure to hyperinsulinism caused persistent Erk/MAPK activity in adipocytes and enhanced insulin resistance in an Egr-1-dependent manner. An elevation in Egr-1 augmented Erk1/2 activation via geranylgeranyl diphosphate synthase (GGPPS). Egr-1-promoted GGPPS transcription increased Ras prenylation and caused Erk1/2 activation. The sustained activation of Erk1/2 resulted in the phosphorylation of insulin receptor substrate-1 at Serine 612. Phosphorylation at this site impaired insulin signaling in adipocytes and reduced glucose uptake. The loss of Egr-1 function, knockdown of GGPPS, or inhibition of Erk1/2 activity in insulin-resistant adipocytes restored insulin receptor substrate-1 tyrosine phosphorylation and increased insulin sensitivity. Our results suggest a new mechanism by which the Egr-1/GGPPS/Erk1/2 pathway is responsible for insulin resistance during hyperinsulinism. This pathway provides a new therapeutic target for increasing insulin sensitivity: inhibiting the function of Egr-1.

Type 2 diabetes mellitus (T2DM) has an intersecting underlying pathology with thyroid dysfunction. The literature is punctuated with evidence indicating a contribution of abnormalities of thyroid hormones to type 2 DM. The most probable mechanism leading to T2DM in thyroid dysfunction could be attributed to perturbed genetic expression of a constellation of genes along with physiological aberrations leading to impaired glucose utilization and disposal in muscles, overproduction of hepatic glucose output, and enhanced absorption of splanchnic glucose. These factors contribute to insulin resistance. Insulin resistance is also associated with thyroid dysfunction. Hyper- and hypothyroidism have been associated with insulin resistance which has been reported to be the major cause of impaired glucose metabolism in T2DM. The state-of-art evidence suggests a pivotal role of insulin resistance in underlining the relation between T2DM and thyroid dysfunction. A plethora of preclinical, molecular, and clinical studies have evidenced an undeniable role of thyroid malfunctioning as a comorbid disorder of T2DM. It has been investigated that specifically designed thyroid hormone analogues can be looked upon as the potential therapeutic strategies to alleviate diabetes, obesity, and atherosclerosis. These molecules are in final stages of preclinical and clinical evaluation and may pave the way to unveil a distinct class of drugs to treat metabolic disorders.

BackgroundThe prevalence of hypertension and diabetes, which often coexist and significantly contribute to the burden of noncommunicable diseases (NCDs), is increasing in India. This study examines the sex-stratified prevalence, coexistence, and bidirectional risks of hypertension and diabetes across states with varying epidemiological transition levels (ETLs) and identifies high-burden hotspots.MethodsThis study analysed data from the fifth round of the National Family Health Survey, covering 614,426 women and 556,199 men aged 30 years and above, with biomarker information on both diabetes and hypertension. The age-standardized prevalence was estimated, and adjusted risk ratios (ARRs) were obtained on multivariate logit scale. Bivariate maps, spatial autocorrelation and hotspot analyses were conducted using ArcGIS Pro to identify geographic clusters associated with twin epidemics.ResultsIndividuals diagnosed with hypertension or diabetes were, on average, nearly a decade older than those without. Hypertension prevalence was 30.3% (95%CI:30.14–30.48) among men and 28.6% (95%CI:28.47–28.79) among women, whereas diabetes prevalence was at 19.7% (95%CI:19.58–19.88) in men and 17.4% (95%CI:17.22–17.50) in women. Among individuals with diabetes, 43.1% (95%CI:42.67–43.53) of men and 43.9% (95%CI:43.48–44.36) of women had hypertension, whereas 28.1% (95%CI:27.75–28.37) of hypertensive men and 26.6% (95%CI:26.33–26.93) of hypertensive women were diabetic. Hotspots for twin epidemics were identified in coastal regions, including the southern states with high ETLs, as well as the northern states with high-ETLs and the country’s northeastern region. ARR estimates revealed that the risk of hypertension among individuals with diabetes was 39% higher (95%CI:1.38–1.40) in men and 41% higher (95%CI:1.39–1.42) in women than in individuals without diabetes. Similarly, the risk of diabetes among individuals with hypertension was 51% higher (95%CI:1.49–1.52) in men and 55% higher (95%CI:1.53–1.57) in women than in individuals without hypertension.ConclusionOur findings highlight the progressive nature of the twin epidemics of diabetes and hypertension, with an increased risk of onset associated with advanced age. The presence of one condition substantially elevates the likelihood of developing the other, highlighting their bidirectional relationship. Achieving Sustainable Development Goal target 3.4 requires addressing these intersecting epidemics as a unified entity for effective management. Targeted interventions should prioritise high-burden hotspots for integrated care strategies to mitigate the twin epidemics of diabetes and hypertension.

Variation in metabolic and cardiovascular risk in women with different polycystic ovary syndrome phenotypes

Diabetes and thyroid diseases are caused by endocrine dysfunction and both have been demonstrated to mutually impact each other. Variation in thyroid hormone levels, even within the normal range, can trigger the onset of type 2 diabetes mellitus (T2DM), particularly in people with prediabetes. However, the available evidence is contradictory.The purpose of this review is to understand the pathological relationship between thyroid-related disorders and T2DM.T2DM in thyroid dysfunction is thought to be caused by altered gene expression of a group of genes, as well as physiological abnormalities that result in decreased glucose uptake increased, splanchnic glucose absorption, disposal in muscles, increased hepatic glucose output. Additionally, both hyperthyroidism and hypothyroidism can cause insulin resistance. Insulin resistance can develop in subclinical hypothyroidism as a result of a reduced rate of insulin-stimulated glucose transfer caused by a translocation of the glucose transporter type 2 (GLUT 2) gene. On the other hand, novel missense variations in (Thr92Ala) can cause insulin resistance. Furthermore insulin resistance and hyperinsulinemia resulting from diabetes can cause culminate in goitrous transformation of the thyroid gland.Thyroid-related diseases and T2DM are closely linked. Type 2 diabetes can be exacerbated by thyroid disorders, and diabetes can worsen thyroid dysfunction. Insulin resistance has been found to play a crucial role in both T2DM and thyroid dysfunction. Therefore, failure to recognize inadequate thyroid hormone levels in diabetes and insulin resistance in both conditions can lead to poor management of patients.