DM Abdullah fasa Bani Issa aaaaaa(4).pptx

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1. Prepared by Captain :Abdullah Bani Issa Diabetes Mellitus

2. Objective - Over view of DM . - Definition of DM . - Prediabetes . - Type of DM . - Complication of DM . - Type of insulin . - Hypoglycemia .

3. Prevalence of diabetes globally * The global diabetes prevalence in 2019 is estimated to be 9.3% (463 million people) , rising to 10.2% (578 million) by 2030 and 10.9% (700 million) by 2045 . * The global prevalence of impaired glucose tolerance is estimated to be 7.5% (374 million) in 2019 and projected to reach 8.0% (454 million) by 2030 and 8.6% (548 million) by 2045 . * Just under half a billion people are living with diabetes worldwide and the number is projected to increase by 25% in 2030 and 51% in 2045 . IDF, diabetes research and clinical practice 157 (2021) 107843

4. A huge and growing global problem

5. The prevalence of Diabetes in Jordan is considered the highest in the region and one of the highest in the world . Almost 374,100 Jordanian adults were known to have diabetes in 2015 . 9.1% of the adult population . More than 3,111 Jordanian adults were reported dead in 2015 from diabetes related diseases . An average of 8.5 deaths per day . Diabetes in Jordan Medical Update and Patient Education Training

6. ** In Jordan the overall age - standardized prevalence rate ( < 25 years) of diabetes increased from 13.1% in 1994 17.1% in 2004 22.2% in 2009 . ** Ajlouni K.et al. Time trends in diabetes mellitus in Jordan between 1994 and 2017. Diabet Med. 36, 1176-1182.(2019) International Diabetes Federation. IDF Diabetes Atlas. 7th ed. Brussels, Belgium, Update Suleiman AK. A prospective study assessing the etiology of Diabetes mellitus among Jordanian patients. Diab Met Syndr : Clin Res Rev (2021), 23.7% in 2017

7. Introduction * The pancreas is both an exocrine gland that produces the digestive enzymes & an endocrine gland . * The endocrine pancreas in the adult human consists of approximately 1 million islets of Langerhans interspersed throughout the pancreatic gland . * The islets of Langerhans contain four main cell types, all of which secrete peptide hormones :- 1 . B (or β) cells secrete insulin . 2 . A cells secrete glucagon . 3 . D cells secrete somatostatin . 4 . F cells secrete pancreatic polypeptide (the function of which is unknown) .

8. prediabetes

9. DEDFINTION OF PREDIABETES * People with prediabetes have impaired fasting glucose (IFG) , impaired glucose tolerance (IGT) , or both — conditions where blood glucose levels are higher than normal but not high enough to be classified as diabetes .

10. Definitions FPG 2-h PPG (OGTT) 126 60 80 100 120 140 160 180 200 Plasma glucose (mg/dL) Normal Diabetes Mellitus 240 220 Diabetes Mellitus Normal IGT IFG ADA. Diabetes Care. 2021;27:S5-S10

11. New ACE/AACE Guidelines * A diagnosis of prediabetes can be made by any of 3 criteria : (a) IFG with glucose levels of 100 to 125 mg/dL (5.6 - 6.9 mmol / L) . (b) IGT with glucose levels of 140 to 199 mg/ dL (7.8-11 mmol / L) after a 75 g oral glucose load . (c) Metabolic syndrome diagnosed by the NCEP ATP III * criteria . *National Cholesterol Education Program Adult Treatment Panel III ENDOCRINE PRACTICE Vol 14 No. 7 October 2021

12. Risk Factor Defining Level Abdominal obesity (waist circumference) Men >102 cm ( > 40 in ) Women > 88 cm ( >35 in ) Triglycerides  150 mg/dL HDL cholesterol Men < 40 mg/dL Women < 50 mg/dL Blood pressure 130/85 mm Hg Fasting glucose 100 mg/dL NCEP ATP III Identification of the Metabolic Syndrome

13. Positive diagnosis is based on the presence of two or more of the metabolic syndrome criteria.

14. ** Hemoglobin A1C values between 5.7 and 6.4 percent have also been considered prediabetes. 6.4 5.7 Hemoglobin A1C Diabetes Mellitus Normal Pre DM The test should be performed in a laboratory using a method that is certified by the National Glycohemoglobin Standardization Program (NGSP)

15. * People with prediabetes are 5 - 15 times more likely to develop type 2 diabetes than are people with normal glucose values .

16. The risk for both macrovascular and microvascular complications increases across the distribution of blood glucose concentrations well below the overt DM, and the risk is more strongly associated with post-challenge hyperglycemia than fasting glucose levels. Diabetes 53:2095–2100, 2021

17. Results from large prospective studies make it clear that aggressive modification of diet and exercise can prevent or slow the progression from prediabetes to diabetes . Treatment ENDOCRINE PRACTICE Vol 14 No. 7 October 2021

18. Studies also showed that diet and exercise modification were significantly more effective in diabetes risk reduction than pharmacological glucose reduction with metformin . ENDOCRINE PRACTICE Vol 14 No. 7 October 2021

19. Algorithm for the metabolic management of type 2 diabetes. Lifestyle intervention should be reinforced at every visit.

20. Diabetes Care.  2021;29(8):1963-1972 Algorithm for the metabolic management of type 2 diabetes. Lifestyle intervention should be reinforced at every visit. This line of treatment should start at the prediabetes stage even before diabetes is diagnosed .

21. What is Diabetes? * A metabolic disorder characterized by elevated blood glucose concentration due to: 1. Defects in insulin production . 2. Destruction of beta cells  Autoimmune or other reasons . 3. Insulin insensitivity  Insulin Resistance . 4. Impaired action of insulin on target tissues . -- which causes hyperglycemia, disturbances of carbohydrate, fat and protein metabolism, and a constellation of chronic complications .

22. Normal blood glucose regulation Interplay between insulin and glucagon 1. Figure adapted from Roder P-V et al. Exp Mol Med. 2021;48:e219; 2. Kahn S-E et al. Lancet. 2021;383:1068–1083. * Low blood glucose levels :- Glucagon is secreted and - Promotes glycogen breakdown (glycogenolysis) 1 * High blood glucose levels :- Insulin is released and - Triggers glucose uptake into muscle and adipose tissues 1 - Promotes glycogen formation (glycogenesis) 1 - Inhibits glucose production (gluconeogenesis) 2 Normal blood glucose levels: 4-6 mM Blood glucose Insulin Glycogenesis Gluconeogenesis Glucose uptake Blood glucose to normal levels Blood glucose to normal levels Glycogenolysis Gluconeogenesis Glucagon Blood glucose

23. Risk Factors Leading to Diabetes Medical Update and Patient Education Training modifiable and non modifiable

24. * Symptoms of Diabetes :-

25. I. Classification and Diagnosis

26. * Type 1 diabetes - β -cell destruction . * Type 2 diabetes - Progressive insulin secretory defect . * Other specific types of diabetes - Genetic defects in β -cell function, insulin action . - Diseases of the exocrine pancreas . - Drug or chemical-induced . * Gestational diabetes mellitus (GDM) Classification of Diabetes ADA. I. Classification and Diagnosis. Diabetes Care 2021;36(suppl 1):S11.

27. Criteria for the Diagnosis of Diabetes ADA. I. Classification and Diagnosis. Diabetes Care 2021;36(suppl 1):S13; Table 2. A1C ≥ 6.5% OR OR OR Fasting plasma glucose (FPG) ≥ 126 mg / dL (7.0 mmol / L) 2-h plasma glucose ≥ 200 mg / dL (11.1 mmol / L) during an OGTT A random plasma glucose ≥ 200 mg/dL (11.1 mmol / L)

28. * In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing. ADA. I. Classification and Diagnosis. Diabetes Care 2021;36(suppl 1):S13; Table 2. 1. A1C ≥ 6.5% The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay *

29. Mean plasma glucose Mean plasma glucose A1C (%) mg/dL mmol/L 6 126 7.0 7 154 8.6 8 183 10.2 9 212 11.8 10 240 13.4 11 269 14.9 12 298 16.5 ** Correlation of A1C with Average Glucose (AG) ** ADA. V. Diabetes Care. Diabetes Care 2021;36(suppl 1):S19; Table 8. These estimates are based on ADAG data of ~2,700 glucose measurements over 3 months per A1C measurement in 507 adults with type 1, type 2, and no diabetes. The correlation between A1C and average glucose was 0.92. A calculator for converting A1C results into estimated average glucose (eAG), in either mg/dL or mmol/L, is available at http://professional.diabetes.org/eAG.

30. *In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing. ADA. I. Classification and Diagnosis. Diabetes Care 2021;36(suppl 1):S13; Table 2. 2. Fasting plasma glucose ( FPG ) ≥ 126 mg/dL (7.0 mmol/L) Fasting is defined as no caloric intake for at least 8 h *

31. *In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing. ADA. I. Classification and Diagnosis. Diabetes Care 2021;36(suppl 1):S13; Table 2. 3. 2 - h plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during an OGTT ** The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water * ** In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥ 200 mg/dL (11.1 mmol/L)

32. II. Testing for Diabetes in Asymptomatic Patients

33. * Consider testing overweight/obese adults (BMI ≥ 25 kg/m 2 ) and who have one or more additional risk factors . - In those without risk factors, begin testing at age 45 years (B) * If tests are normal - Repeat testing at least at 3-year intervals (E) * Use A1C, FPG, or 2-h 75-g OGTT (B) * In those with prediabetes - Identify and, if appropriate, treat other CVD risk factors (B) ** Recommendations: Testing for Diabetes in Asymptomatic Patients ADA. II. Testing for Diabetes in Asymptomatic Patients. Diabetes Care 2021;36(suppl 1):S13.

34. ** Criteria for Testing for Diabetes in Asymptomatic Adult Individuals (1) *At-risk BMI may be lower in some ethnic groups. 1. Testing should be considered in all adults who are overweight (BMI ≥ 25 kg/m 2 *) and have additional risk factors :- ADA. Testing for Diabetes in Asymptomatic Patients. Diabetes Care 2021;36(suppl 1):S14; Table 4. - Physical inactivity . - First-degree relative with diabetes . - High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander) . - Women who delivered a baby weighing > 9 lb or were diagnosed with GDM .

35. - Hypertension ( ≥ 140/90 mmHg or on therapy for hypertension ) . - HDL cholesterol level < 35 mg/dL ( 0.90 mmol/L ) and/or a triglyceride level > 250 mg/dL ( 2.82 mmol/L ) . - Women with polycystic ovary syndrome ( PCOS ) . - A1C ≥ 5.7% , IGT , or IFG on previous testing . - Other clinical conditions associated with insulin resistance (e.g., severe obesity , acanthosis nigricans ) . - History of CVD .

36. ADA. Testing for Diabetes in Asymptomatic Patients. Diabetes Care 2021;36(suppl 1):S14; Table 4. Criteria for Testing for Diabetes in Asymptomatic Adult Individuals (2) 2. In the absence of criteria (risk factors on previous slide) , testing for diabetes should begin at age 45 years . 3. If results are normal , testing should be repeated at least at 3-year intervals , with consideration of more frequent testing depending on initial results (e.g., those with prediabetes should be tested yearly) , and risk status .

37. D.M. Type 1 ** Epidemiology in US in < 19 years of age population :- 1. Incidence: 16/100,000/years . 2. Prevalence: 140/100,000 . 3. Mean age of onset: 11 years in F / 12.5 years in M . 4. Incidence by gender : - - < 5 years : increased in males . - 5 - 10 years : increased in females . - 11- 19 years : equal in males and females .

38. ** ISLET CELLS ANTIBODIES : - - A heterogeneous group of AB against a variety of cytoplasmic islet cell antigens . - Not exclusively against Beta cells . Other islet cells are also targets . - Highly positive esp. in the pre - diabetic phase . - More positive at onset than later . - Positivity decreases rapidly with duration of diabetes .  

39. ** ISLET CELLS ANTIBODIES :- DURATION OF DIABETES % POSITIVE 1-4 WEEKS 60-95 % *   3-9 MONTHS 50 %   1-10 YEARS < 25 %   *** Positive ICA correlate with declining C-peptide levels & increasing insulin requirements    

40. ANTI GLUTAMIC ACID DECAROXYLASE ( GAD) AB   Anti GAD Antibodies ** Present in 75 - 84 % of recent onset DM type 1 .  

41. Hyperglycemia ** Pathogenesis of Type 1 Diabetes : One Defect Unrestrained glucose production Impaired glucose clearance No hepatic insulin effect No muscle/fat insulin effect Absent insulin secretion Glycaosuria More glucose enters the blood Less glucose enters peripheral tissues

42. ** D.M. Type 1 - Pathogenesis 1. Genetic factors : A - MHC : predisposing genes HLA-DR3, DQB1*0201 or DR4,DQB1*0302 . protective: DQB1*0602 . B - Non- MHC genes: At least 19 genes have been identified, 3 of them mapped to chromosomes: 11, 15, 2 .

43. 2. Environmental factors: e.g. Coxakie virus infection . 3. Autoimmune: A) T- lymphocyte - mediated destruction ( inslinitis ) . B) Markers, not causative: Autoantibodies ( ICA, IAA, GAD) .

44. ** The combination of all those factors ultimately leads to β - cell destruction , which is an insidious process that may take up to 10 yrs before completion; once the β - cell mass is < 5 - 10% of its original amount , symptoms of diabetes become manifest .

45. * Type 1 diabetes :- - Type 1 diabetes is a disease in which the pancreas does not produce any insulin . ** Insulin is an important hormone that helps your body to control the level of glucose (sugar) in your blood .

46. - Roughly 10 per cent of people living with diabetes have type 1, insulin-dependent diabetes . ** Type 1 diabetes generally develops in childhood or adolescence, but can also develop in adulthood . ** People with type 1 need to inject insulin or use an insulin pump to ensure their bodies have the right amount of insulin . 

47. “Shortly after the onset of the disease, there may follow a brief period of a spontaneous remission” called: “The honey-moon period”. * The honey - moon period :-

48. * The “honeymoon period” in type 1 diabetes mellitus :-   1. Characterized by evidence of recovery of endogenous insulin secretion . [ presence of C-peptide in serum ] -- Insulin requirements become less and less, sometimes none .   2. Lasts for 2-3 months up to one year . Thereafter , the disease re-appears and the state of insulin dependency becomes permanent for life .  

49. * Management Goals :- - Controlling symptoms of hyperglycemia . - Avoiding acute complications of severe hyperglycemia ( HNK coma and DKA ) . - Avoiding hypoglycemia . - Reducing rate of chronic complications .

50. ** Treatment for type 1 :- only Insulin

51. -- Premixed insulin associated with marked glucose variability alternating hyperglycemia and hypoglycemia which is associated with diabetes complications and this appear with using recent technology in diabetes like flash glucose monitoring or real time monitoring free style libre and Dexcom . ** We should start basal bolus regimen . -- Bolus insulin either regular or rapid acting insulin with meals . -- Basal insulin to control fasting blood glucose and glucose between meals .

52. ** Starting dose: - 0.5 units per kg per day. - Sometimes we increase starting dose to 0.7 units per kg up to unit per kg in prepubertal and pubertal children to overcome insulin resistance but over all I prefer to start low dose insulin and increase gradually to overcome hypoglycemia especially nocturnal hypoglycemia . ** Dose is divided into 50 percent bolus and 50 percent basal . 50 percent bolus is divided over 3 meals and 50 percent basal over one or two doses . -- And percent may be 30 percent basal and 70 percent bolus if you are using regular insulin which may have some basal effect . ** So lets take a look about different types of insulin .

53. ** FACTORS AFFECTING INSULIN DOSE :- 1. Age . 2. Weight . 3. Pubertal stage . 4. Duration of diabetes . 5. State of inject sites . 6. Nutritional intake and distribution . 7. Exercise pattern . 8. Daily routine . 9. Results of SMBG and HbA1C . 10. Intercurrent infections .

54. - Children with new-onset type 1 diabetes and their families require intensive diabetes education by an interprofessional pediatric diabetes health-care (DHC) team . -- Education topics should include:- 1. Prevention, detection and treatment of hypoglycemia . 2. Insulin action and administration . 3. Dosage adjustment . 4. Blood glucose and ketone testing . 5. Sick-day management . 6. Prevention of DKA . 7. Nutrition and exercise . * Education – Key Message :- 2021 Diabetes Canada CPG – Chapter 34. Type 1 Diabetes in Children & Adolescents DKA, diabetic ketoacidosis

55. * Late-Onset Type 1 Diabetes :- - About half of patients with type 1 diabetes are diagnosed after age 18 . - Autoimmune process may differ and is slower . - Often mistaken for type 2 diabetes—may make up 10% – 30% of individuals diagnosed with type 2 diabetes . - Can be identified by ICA or GAD antibodies . - Oral agents are usually ineffective—insulin therapy is eventually required .

56. * “Type 1.5” DM :- - Begins as Type 1 with DKA . - Later becomes non-insulin dependent . - No HLA predisposition . - No autoimmunity . - Occurs in certain ethnic groups, e.g. African- Americans .

57. * DM type 2 :- - Type 2 diabetes is a disease in which your body cannot make enough insulin (a hormone that helps control the amount of glucose or sugar in your blood) , or does not properly use the insulin it makes . - Type 2 diabetes is caused by several different risk factors and accounts for 90% of diabetes .

58. 58 * Major Pathophysiologic Defects in Type 2 Diabetes :- Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus . 14th ed. Lippincott Williams & Wilkins; 2021 :145–168. Hepatic glucose output Insulin resistance Glucose uptake Glucagon ( α cell) Insulin ( β cell) Liver Hyperglycemia Islet-Cell Dysfunction Muscle Adipose tissue Pancreas

59. At diagnosis, pancreatic islet function is already declining

60. DeFronzo RA. Diabetes. 2021 : 773 – 795 .

61. * Type 2 Diabetes: Two Defects Genes Genes Type 2 diabetes Insulin resistance Impaired Insulin Secretion ± Environment ± Environment IGT IGT

62. Evolution of diabetes Normal Compensation phase Diabetes DeFronzo R.A. et al., Diabètes Care (2021) * Insulin Resistance & Insulin Deficiency :- 2 strongly linked mechanisms At the time of diagnosis , both defects are already combined Insulin resistance Fasting blood glucose Insulin secretion

63. β -Cell Function Declines Regardless of Intervention in T2DM Adapted from UKPDS Group. Diabetes . 2021;44:1249-1258. 20 40 60 80 100 –5 –4 –3 –2 –1 1 2 3 4 5 6 Years Since Diagnosis Sulfonylurea Diet Metformin β-Cell Function (%)* Progressive loss of β -cell function occurs prior to diagnosis * β -cell function measured by HOMA

64. UKPDS: Improving HbA 1c Control Reduced Diabetes-Related Complications UKPDS=United Kingdom Prospective Diabetes Study. Data adjusted for age, sex, and ethnic group, expressed for white men aged 50–54 years at diagnosis and with mean duration of diabetes of 10 years. Stratton IM et al. UKPDS 35. BMJ 2021;321:405–412. EVERY 1% reduction in HbA 1c REDUCED RISK (P<.0001) 1% Diabetes-related deaths Myocardial infarctions Microvascular complications Amputations or deaths from peripheral vascular disorders 21% 14% 37% 43% Relative Risk N=3642 64

65. 65 ADA and IDF Guidelines: Treatment Goals for HbA 1c , FPG, and PPG Parameter Normal Level ADA Goal IDF Goal FPG, mg/dL (mmol/L) < 100 ( < 5.6 ) 70 –130 ( 3.9 –7.2) < 100 ( < 5.5 ) PPG, mg/dL (mmol/L) < 140 ( < 7.8 ) < 180 ( < 10.0 ) < 140 ( < 7.8 ) HbA 1c 4% – 6% < 7%* < 6.5% a a Reference to a nondiabetic range of 4.0% to 6.0% using a DCCT-based assay. ADA=American Diabetes Association; IDF=International Diabetes Federation. American Diabetes Association. Diabetes Care. 2021;32(suppl 1):S13–S61; International Diabetes Federation. 2021:1 – 32. Buse JB et al. In: Williams Textbook of Endocrinology,11th ed. Philadelphia: Saunders; 2021:1329–1389.

66. * Diet and Exercise : - At least 5% wt loss is recommended - Moderate to vigorous intensity aerobic activity for 150 min/wk * Oral Hypoglycemic Agents. - For type 2 DM * Insulin. - For type 1 DM and pregnant diabetic Pt . * Blood sugar control :-

67. * Oral Hypoglycemic Agents :- 1. Metformin ** Mechanism of action :- - increases insulin sensitivity . - decreases hepatic gluconeogenesis . - may also reduce gastrointestinal absorption of carbohydrates . ** Side effects :- - gastrointestinal upsets are common (nausea, anorexia, diarrhea) . - vitamin B12 deficiency . - lactic acidosis with severe liver disease or renal failure .

68. 2. Alpha glucosidase inhibitors ** Mechanism of action :- - inhibits intestinal α- glucosidase , which therefore delays the digestion and absorption of starch and sucrose. ** Side effects :- - Diarrhea - Abdominal pain - Bloating - Flatulence ** Examples :- - Acarbose - Miglitol

69. 3. Thiazolidinediones ** Mechanism of action :- - Lead to increased peripheral insulin sensitivity, and improve glucose uptake . - Increase metabolism of free fatty acids . ** Side effects :- - Weight gain . - liver impairment . - Fluid retention . - Increased risk of osteoporotic fractures bladder cancer . ** Examples :- - Pioglitazone

70. 4. Sulphonylureas ** Mechanism of action :- - Act by enhancing pancreatic islet cell function promotes insulin release . ** Side effects :- - Hypoglycemia . - Weight gain . - Syndrome of inappropriate ADH secretion . - Bone marrow suppression . - Liver damage (cholestatic) . - Photosensitivity . - Peripheral neuropathy .

71. 4. Sulphonylureas ** Examples :- - Glimepiride (Amaryl) . - Glibenclamide ( daonil ) . - Gliclazide . - Glipizide .

72. 5. Meglitinides ** Mechanism of action :- - Act by enhancing pancreatic islet cell function promotes insulin release . ** Side effects :- - Hypoglycemia . - Weight gain . ** Examples :- - Repaglinide . - Nateglinide .

73. 6. Glucagon-like peptide-1 (GLP-1) ** Mechanism of action :- - Increase insulin secretion . - Inhibit glucagon secretion . - Inhibits glucose production in the liver . - Slows gastric emptying . - Suppresses appetite . ** Side effects :- - Nausea . - Vomiting . - Pancreatitis .

74. 6. Glucagon-like peptide-1 (GLP-1) ** Examples :- - Exenatide . - Liraglutide .

75. 7. (DPP-4) inhibitors ** Mechanism of action :- - Dipeptidyl peptidase-4 (DPP-4) inhibitors . - Induce Glucose dependent glucagon suppression . ** Examples :- - Saxagliptin . - Linagliptin . - Sitagliptin . - Vildagliptin . ** Side effects :- - GI disturbance .

76. 8. SGLT2 inhibitors ** Mechanism of action :- - reversibly inhibit (SGLT2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion. ** Side effects :- - Genital infection (secondary to glycosuria) . - Diabetic ketoacidosis . - Increased risk of bone fracture . ** Examples :- - Canagliflozin . - Dapagliflozin . - Empagliflozin .

77. MODY * MODY :- is non-insulin requiring form of diabetes , occurring in children and young adults , resulting from genetic defect in beta-cell function , and inherited in autosomal dominant trait (AD) .

78. * MODY :- ** MATURITY ONSET DIABETES OF THE YOUNG (MODY) .   - Clinical presentation partly similar to type 2 DM but occurring in young age group-mostly adolescents .  - Autosomal dominant inheritance; 5 different gene defects described All relatively rare .  

79. Clinical Features Type 1 No No Yes Type 2 Yes Yes No MODY No No No Obesity Insulin resistance Autoimmunity

80. - Nonketotic onset of DM . - Diagnosis before the age of 25 years . - Autosomal dominant trait of inheritance . - Treated successfully without insulin ( Lancet 2021-V345 ) . * Tattersall & Fajans criteria of diagnosis :-

81. -- Mutation in transcription factors genes (6 types) :- * 5 Hepatocyte Nuclear Factor (HNF) . * Insulin Promoter Factor (IPF) . * Mutation in glucokinase enzyme gene (1type) . - Transcription factors:- intracellular protein that regulate genes transcription into in mRNA (gene expression) . Molecular Basis for MODY

82. * Genetic heterogeneity in MODY :- MODY Type Gene Clinical Features of Heterozygous State MODY 1 HNF-4 α Diabetes ; microvascular complication , reductions in serum triglycerides , apolipoproteins . MODY 2 Glucokinase Impaired fasting glucose , impaired glucose tolerance , diabetes , normal proinsulin -to-insulin ratio in serum . MODY 3 HNF-1 α Diabetes , microvascular complication , renal glycosuria . MODY 4 IPF-1 Diabetes . MODY 5 HNF-1 β Diabetes ; renal cysts and renal dysfunction , internal genital . abnormalities MODY 6 NeuroD1, OR BETA2 Diabetes

83. * Other specific causes of diabetes in children :- 1. Metabolic: Hypernatremia . 2. Infections: Congenital Rubella . 3. Drugs: Many . 4. Mitochondrial myopathies .

84. 5. Selected genetic neuromuscular disorders : - - Wolfram syndrome . - Friedreich ataxia . - Alstrom syndrome . - Laurnce -Moon-Biedl syndromes .

85. Gestational - Diabetes Mellitus

86. * Introduction :- - Gestational Diabetes Mellitus (GDM) is defined as Impaired Glucose Tolerance (IGT) with onset or first recognition during pregnancy . - Worldwide, one in 10 pregnancies is associated with diabetes, 90% of which are GDM . - Undiagnosed or inadequately treated GDM can lead to significant maternal & foetal complications . - Women with GDM and their off-springs are at increased risk of developing Type 2 diabetes later in life .

87. * Patho-physiology :- - GDM is characterised by hyper - Insulinaemia and insulin resistance . - In first trimester and early second trimester , increased insulin – due to high levels of oestrogen . - In late second and early third trimesters , insulin resistance - due to a number of antagonistic hormones especially, placental lactogen, leptin, progesterone, prolactin, cortisol and adiponectin .

88. Implications of Diabetes in Pregnancy * Doubles ….. risk of serious injury at birth . * Triples ….. The likelihood of Caesarean delivery . * Quadruples ….. The incidence of Neonatal Intensive Care Unit admission .

89. Pregnancy and Diabetes- The vicious cycle Pregnancy Diabetes Mellitus

90. * Effects of Pregnancy on Diabetes :- - During pregnancy, there is altered carbohydrate metabolism and impaired insulin action . - Insulin requirement increases as pregnancy advances . - Accelerated starvation----rapid activation of lipolysis with short period of fasting . - Higher risks of Ketoacidosis complications .

91. 1. Respiratory Distress Syndrome . 2. Polydydramnios . 3. Foetal macrosomia . 4. Erb’s Palsy . 5. Birth asphyxia . 6. Abortion/Intra uterine death . 7. Neonatal hyperbilirubinemia . 8. Congenital malformations . * Effect of Diabetes on Pregnancy :

92. GDM: Risk Factors - Age >25 years . - BMI > 25kg/m ² . - Increased weight gain during pregnancy . - Previous history of large for gestational age infants . - History of GDM during previous pregnancies . - Ethnic group ( East Asian, Pacific Island ancestry) . - Elevated fasting or random blood glucose levels during pregnancy . - Family history of diabetes in first degree relatives . - History of metabolic X syndrome . - History of type I or type II Diabetes Mellitus . - Unexplained fetal loss .

93. GDM: Maternal Complications During Pregnancy Abortion Preterm labour (due to infection or polyhydramnios ) Pre- eclampsia Polyhydramnios Maternal distress due to oversized fetus and polydramnios Microangiopathy - Nephropathy, retinopathy, neuropathy Large vessel disease Coronary artery disease Thromboembolic disease Infection Hypo and hyperglycaemia During labour Prolonged labour Shoulder dystocia Perineal injuries PPH Operative interference Increased risk of Caesarean delivery Puerperium Puerperal sepsis Lactational failure

94. GDM: Foetal Complications ** 1st Trimester Congenital abnormalities - Cardiac : ASD, VSD - NTD - Sacral agenesis/ CRS - PCKD - Renal agenesis - Duodenal atresia - Tracheo - esophageal fistula ** 2nd Trimester - Macrosomia During delivery - Birth asphyxia - Shoulder dystocia After delivery - RDS - Hypoglycaemia - Polycythaemia - neonatal jaundice

95. GDM: Foetal Complications - Congenital abnormalities . - Macrosomia . - Birth asphyxia . - Shoulder dystocia . - RDS . - Hypoglycaemia . - neonatal jaundice .

96. Signs - Elevated serum glucose . - Glycosuria . - Ketonuria . - Elevated glycosylated haemoglobin (HBA1C) . GDM: Diagnosis Symptoms - A symptomatic . - Polyuria , polydipsia , polyphagia . - Fatigue and weight loss . - Women with established diabetes may have retinopathy or neuropathy .

97. Principles of Management (National Guidelines for Diagnosis and Management of GDM-2021)

98. * Who should be tested ? - The first testing - first antenatal contact as early as possible . - The second testing “ 24 – 28 ” weeks of pregnancy if the first test is negative . - At least 4 weeks gap between the two tests .

99. * How to Test ? - Single step testing - 75 gm oral glucose & measure plasma glucose 2 hour after ingestion . - 75 gm glucose mixed with 300 ml water ingested whether the PW comes in fasting or non-fasting state . - A plasma standardised glucometer should be used to evaluate blood glucose 2 hours after the oral glucose load . * The threshold plasma glucose level of ≥ 140 mg/dl is taken as cut off for diagnosis of GDM .

100. Sulfonylureas Insulin secretagogues Glipizide, glyburide Increase insulin secretion, decrease hepatic glucose production with resultant reversal or hyperglycaemia and indirect improvement of insulin sensitivity Meglitinides Biguanides Decrease insulin resistance Alpha glucosidase inhibitors eg acarbose ) Decrease intestinal absorption of starch and glucose Thiazolidinediones Eg rosiglitazone and pioglitazone ORAL HYPOGLYCAEMIC AGENTS Not Recommended in National Guidelines - only Insulin to be used

101. Target Blood Glucose Values

102. Exercise * Experts recommend that women with GDM should exercise regularly to control blood glucose levels . * but an improvement in clinical outcomes has not been demonstrated from compliance with this recommendation .

103. Insulin Therapy - Traditionally, insulin is used if dietary management does not maintain blood glucose at normal levels . - Insulin may be initiated at 0.7 U/kg actual body weight/d given in divided dosages: two-thirds of the daily dosage before breakfast and the remainder of the dosage before dinner . - Insulin therapy require close monitoring and adjustment based on blood glucose levels , meal choices , and activity levels .

104. Summary- Key Points - Universal testing of all PW for GDM . - Testing recommended twice in pregnancy at 1st antenatal visit and then at 24-28 weeks of gestation . - Single step 75 g 2 hr PPPG test to be performed . - PW testing positive (2 hr PPPG > 140mg/dl) should be started on MNT for 2 weeks . - If 2 hr PPPG ≥ 120 mg/dL after MNT , medical management (Insulin therapy) of PW to be started . - PW to be monitored by 2 hr PPPG throughout pregnancy .

105. 1. ISPAD : International Society For Pediatric and Adolescent 2021 . 2. ADA : American Diabetes Association 2021 . * References :-

106. Thank You